الفهرس 
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Abstract
Diethylnitrosamine (DENA) is a hepatocarcinogenic nitrosamine that is present in tobacco smoke, cosmetics, cured meat products, polluted water and pharmaceutical agents. DENA-induced hepatocellular carcinoma is an accepted and broadly-used experimental model that resembles hepatocarcinogenesis in humans.
DENA- induced HCC is a two-stage model characterized by a genotoxic compound that is used as initiator followed by a promotion phase. In this model. DENA is used as an initiator and 2-AAF as a promoting agent.
Much evidence of the preventive effects of isatin has been provided in the present study on DENA/2-AAF-induced HCC.
The adult male Wistar rats of this investigation were allocated into three groups ten for each as follow:
group I (Control group): Rats of this group were intraperitoneally given saline and were also orally supplemented with the equivalent volume of 1% tween 80 (w/v) and CMC (1% w/v) as vehicles.
group II (DENA/2-AAF group): Rats within this group were intraperitoneally
injected with DENA in saline (150 mg/kg) once a week for two weeks. Seven days after the last injection of DENA, 2-AAF (20 mg/kg) suspended in 1% tween 80 was orally given every other day for 3 successive weeks.
group III (DENA/2-AAF + Isatin): Rats received DENA and 2-AAF as described in group II and were also orally treated with isatin (25mg/kg( suspended in 1% CMC every other day from the beginning of the experiment for 20 weeks.
In the current study, the animals treated with DENA/2-AAF demonstrated a significant liver injury displayed by the augmented serum ALT, AST activities and total bilirubin level in addition to the lowered albumin levels. The treatment of
DENA/2-AAF-administered rats with isatin resulted in marked improvements in these hepatic function biomarkers in serum.
The obtained results also revealed a significant increase of CA19.9 and AFP levels in DENA/2-AAF-administered rats. The treatment of DENA/2-AAF- administered rats with isatin efficaciously counteracted these variations.
Administraton of DENA/2-AAF exhibited a significant elevation of liver MDA content and a significant diminution in both liver GSH content and SOD activity in comparison with control rats. The oral supplementation with isatin significantly decreased MDA content and increased both GSH activity and SOD content when compared to DENA/2-AAF-administered rats.
The current data revealed that DENA/2-AAF-administered rats exhibited a significant increase in liver TNF-α, NF-κB p50 and NF-κB p65 protein expression as compared to control group. The treatment of DENA/2-AAF-administered rats with isatin produced a significant decrease in TNF-α, NF-κB p50 and NF-κBp 65 protein expressions.
The protein expressions of liver Nrf2, NQO1 and GSTA2 was significantly decreased in the DENA/2-AAF- treated rats. The treatment of DENA/2-AAF- administered rats with isatin produced a significant up-regulation of Nrf2, NQO1 and GSTA2 protein expressions. Isatin treatment nearly normalized the Nrf2, NQO1 and GSTA2 protein expressions.
The protein expression of Ki67 was significantly increased in liver of DENA/2-AAF-administered rats. The treatment of DENA/2-AAF-administered rats with isatin produced a significant down-regulation of Ki67 protein expression.
The current data revealed that DENA/2-AAF-administered rats exhibited a significant decrease in liver Bcl2 expression as compared to control group. The
treatment of DENA/2-AAF-administered rats with isatin produced a significant increase of Bcl2 protein expression.
The results demonstrated a significant increase in liver apoptotic markers P53 and caspase 3 expressions after the administration of DENA/2-AAF when compared to the control rats. The treatment of DENA/2-AAF-administered rats with isatin produced a significant decline in liver tissue p53 and caspase 3 levels.
These biochemical modifications are concomitant with the liver histopathological examinations in which liver sections from DENA/2-AAF- administered rats showed large altered clear hepatocellular foci surrounded by proliferated oval cells also exhibited oval cells proliferation, fibroblasts proliferation and karyomegally of hepatocytic nuclei. The treatment of these animals with isatin successfully prevented most of these biochemical and histological changes.
In conclusion, isatin has potent preventive effects on DENA/2-AAF-induced HCC and liver damage by improving antioxidant and anti-inflammatory effects. Nevertheless, clinical studies are obligatory to evaluate the safety and the effectiveness of isatin in human beings.